Alkylaminoalkyl esters of alicyclyl-alicyclic carboxylic acids



Patented June 1,949

ALKYLAMINOALKYL ESTEBS OF 101- CLIC CABBOXYLIC ACIDSMarclcGeorgeVanCmJr, Wyoming,

Tiliol'd,Silverton,0

Charles Harmon signers to The Wm.

This invention new esters of gen base alcohols which are of therapeuticvalue,

in general having antispasmodic action on nor-' mal smooth muscle aswell as against histamineinduced, neutotropic. and musculotropic spasmsof the smooth muscle, marked'local anesthetic bio, al-

SJlenellGmpumOlnvcinnatl.0l|io,|.corporation!Delawarev No Drawing. 'MWJ31,1246,

led Nam c ao-4m action which is often a valuable adjunct totheantispasmodic activity and inmany cases is suiflciently pronounced tomake the compounds of :value as local anesthetics, definite sedative action; the property of neutralizing the physiological action oi histaminegenerally, indicating usefulness in combating allergies, and which,

despite their physiological activity, are nevertheless quite free fromundesirable side reactions,

such as irritation-or vasopressor eflects, and have n a suitably lowtoxicity.

The new-compounds oi the invention are the esters of nitrogen basealcohols, i. e., amino or quaternary'ammonium alcohols, with carboxyacids having the formula:

RRiCOOH in which R is a cyclic radical, e. g., aryl, aralkyl oralicyclic, and R1 is alicyclic. Both the radicals represented by R andR1 may be further substituted byother groups such as alkyl groups. wamino groups, hydroxy groups, halogen atoms and the like. The radicals Rand R1 may be directly linked together or joined by a bridging radical,suchas carbonyl (CO), methylene (CH2) monium alcohols, including thoseprepared by the alkylation of tertiary amino alcohols, as by treatmentwith alkyl halides, e. g., ethyl bromide.

The nitrogen base alcoho1 may containone or more basic nitrogen, e. g.,amino. groups, and

, one or more hydroxy groups, at least one amino or quaternary. ammoniumgroup and one hydroxyl group being necessary.

" The new compounds of the invention may be prepared as tree bases or astheir acid addition salts. and the invention includes both forms or thenew compounds. In general. for therapeutic purposeathecompoundswillbeusedinthe form oi their salts. mostcommonly in the form oi thehydrochloride. are oils and thehydrochlorides are white crystallineproducts which are readily purified and conveniently .used. Other salts,such as the phosphates, sulfates, tartrates, glycolates, levulinates,etc.. may be readily prepared, as by' neutralization oi the free basewith the selected acid, and are included within the invention. Ingeneral. because of convenience of preparation, the compounds willordinarily be produced in the form of their salts, but these are readilyconverted to the tree bases by treatment with an alkali such as sodiumcarbonate in the customary way. v

A convenient way oi preparing most of the new compounds is by transorreesteriflcation of the corresponding simple alkyl esters of theselected carboxy acid with an amino alcohol, usually under conditionssuch that there is separation of liberated alcohol by distillation, usinan inert solvent, such as xylene, and advantageously with the use of acatalyst, such as sodium. The reesterification proceeds smoothly andrelatively good yields of the desired products are obtained; Thequaternary ammonium compounds may beprepared-by the alkylation of acorresponding tertiary amino ester, as with an alkyl salt, such as analkyl bromide.

The production of new compounds oi the invention will be illustrated bythe following speciilc examples, but the invention is not limitedthereto.

Example I.-,9-Diethylaminoethyl I-phenulczl- Q clohexanecarbozylatehudrochloride.l55 grams of l-phenylcyclohexanecyanide, 350 cc. ofconcentrated sulfuric acid and 1130 cc. of ethyl alcohol are refluxedvigorously for 48 hours. remaining alcohol is then removed by vacuumdistillation and the residue is poured into 1 liter of ice water. An oilseparates which is extracted 3 times with 200 cc. portions of petroleumether.

the extracts are combined and heated on a steam bath to remove theether. The resulting crude estermay be used directly for thereesterification In general, the tree bases The operation or it may bedistilled-topurifyit first. A mixture oi the ester so obtained, 155grams of p-diethylamin'oethanol and 800 cc. of dry xylene are placed ina reaction vessel with about 2 grams of sodium. The vessel'is heated inan oil bath at 150-160 C. -A xylene-ethanol'azeotrope distills over atabout 78-82 C.over a period formed. When 80-90% 01' the theoreticalamount oi alcohol isobtained in thedistillate .the reaction mixtureis'subjected to 'vacuum'distillation to remove 'most'oi' the xylene andunreacted diethylaminoethanol.

with 500 cc. portions of water. The washed ExampleIV.-p-Dimethylaminethul I-phenplcyclohexanecarbozcylate hpdrochloflda-Bythe use of p dimethylaminoethanol in the reesterifl-- cation operationof Example I, and otherwise i'ollowing the directions of that example,this prod- "uct is obtained in the form of crystals melting at I'm-177C. l

' s and fl-dimethylaminoethanol, and: following theoperation, thisproduct isobt'ainebzi inthe form of The residue is poured into,... 50000.01 benzene which is then extracted 3 times benzene layer is dilutedwith an equal volume of ether and alcoholic hydrochloric acid is-added'until the mixture is acid to Congo red. A white crystalline solid formswhich is dissolved in 300- point where precipitation starts. A few dropsoi butanone are added, the solution is cooled to separate.

yield.

The product exhibits marked"- physiological activity. It is highlyactive as anantispasmodic.

has relatively low toxicity, produces local anesthesia in lowconcentrations, e. g. 1%, for relatively long periods as when instilledin the eye,

has low irritation when-injected subcutaneously, and on administrationproduces sedation. It'may be administered orally or parenterally.

carboxy acidso obtained is subjected to reesteri-" ilcation. withfl-diethylamlnoethanol. The ester obtained is purified, following theprocedure of Example I. The product is finally obtained as melting at139-141 C. in good yields.

. The physiological properties of this product are in general similarExample I.

Example III.fi-Diethylaminoethyl I-a-naphthalenecyclopentanecarbozylatehydrochlo'ride.- To 300 cc. of liquid ammonia containing 0.2 gram offerric nitrate are added 27 grams of sodium strips over a period of 30minutes. 92 grams of a-naphthaleneacetonitrile are then added while thetemperature is maintained at -40 C. 120 grams of 1,4-dibromobutane and.500 cc. of dry ether are then added overa period of 2 hours at -50 C.The ammonia is then removed by evaporation and the residue is heated onthe steam bath for 2 hours. The mixture is then cooled, treated withwater and extracted with 200 cc. portions of' benzene. The benzeneextracts are combined and distilled. At 172-5 C./0.6 mm., 81 grams of1-naphthalenecycio-' pentylcyanide are obtained. Alcoholysis of thisproduct with sulfuric acid and ethyl alcohol followed byreesterificatidn with fi-diethylaminoethanol and working up or theproduct as in Example I gives the desired product as the hydrochloridein the form of crystals melting at 175-176 C.

to those of; the product of ester hydrochloride is obtained in goodyields in v the form o'f'crystals melting at Lil-145 C.

400 cc. of alcohol and diluted with ether to the 1 p -10 C.. andfiltered to recover the crystals'which" The product is'obtained in theform of white needles melting. at 159-160 C., in good Example V. -)8-Dimethylaminoeth jl 1 phenulcvclopentanecarbozylat hydrochlo ide-By theuse of ethyl -'-.1-phenylcyclopentanecarboxylate procedure of Example Igfor the. reesterification white crystalline platelets melting at116-118 C. 1 'Egcample VI. f 1 -Piperidino-2-hydroxu-3- (1phenulcyclohexanecarbozy) mmpane hydrochlorfide.--By the use ofethyl-l-phenylcyclohexanecarboxylate and an excess of l-piperidino-2,3-propanediol in the reesterlfication operation otherwise carried out asin Example I, this mono- Example VII. 1Piperidino-z-phenylurethhydrochloride.--A mixturecontaining 4 parts ofthe free, base 1' piperi'dino2-hydroxy-3-(1"- phenylcyclohexanecarboxy)propane, obtained by'converting the product of Example VI to the freebase-with the use of alkali, 1.6 parts of phenylisocyanate. and80 partsof dry benzene is refluxed for 3 hours. Alcoholic hydrochloric acid isthenvadde'd' until the solution is acid to Congo red, and the mixture iscooled and filtered. The

recovered product is recrystallized from butanone. 1.5 parts of thecrystalline product melting at 162-164? C. is obtained. The illtrate isevaporated to a residue which is recrystallized from 30 parts of water.2 parts of a second racemic modification melting at 6669 C. areobtained.

Example VlII.-1,3 -Bis- (diethylamino) -Z- (1 phenylcyclohemmzecarborry)propane dihzldro- I chloride.-1,3-Bis(diethylamino) -2-propanol andethyl 1-phenylcyclohexanecarboxylate are heated together in xylene withsodium as a catalyst as in v the preceding examples, giving, the esterinthe I f rm I 'd'h r i 135-1 the hydrochloride in the form of white"crystals of a I yd ocmor de meltmg'at 37 C Example IX.4 (1Phenycyclohexanecarberg methyl) 3,4-dimethyleneozyoxazolidine hydrochlo'rz'de.Reesterification of ethyl l-phenylcyclohexanecarboxylate,using 35 parts of this ester, with 44 parts of4-hydroxymethyl-3,4-dimethyleneoxazolidine, as in the preceding examplesgives the above product as the hydrochloride melting at 166-168 C.

Example X.-,8 1-Phenylcyclohezanecarbozy- 32,6" dihydrozy tert.-butylamine hydrochloride-7 parts of the product of the preceding ex- Iample are heated with 350 parts of water for 24 hours on the steam bathwith addition of water to replace that which evaporates. The water is Ithen removed by vacuum distillation and the residue recrystallized frommethanol. The product is obtained in good yield as the hydrochloridemelting at 213 C.

Example XI.B Diethylaminoethyl Z-phenylhudrin'dene 4 2 carbozylatehydrochloride. The alcoholysis of 2;-phenylhydrindene 2 cyaprocedure,but applied to l-phenylcyclobutylcym nlde, gives the above productmelting at 145-146 similar procedure applied tol-phenylcyclopropylcyanide gives the above product as a hygroscopiccrystalline material, the melting point of which scopic nature.

ExampleXIV.-p-Diethplaminoethyl-2-cuclohexylcarbonyl-Ai-cyclohexenecarboaylatehydrochloride.-Reesterificatlon of ethyl2-cyc1ohexylcarboxyl-Ai-cyclohexene carboxylate with fi-dlethylaminoethanol gives this product, M. P. 103- 108' C. Two stereoisomeric formsof this have been isolated, the higher meltinghaving a melting point of118-122 C. and dissolving in about 3 parts of water. The other melts at103-108 C. and dissolves in about 3 parts of water. B-Diethyiaminoethyl2-benzoyl A4 cyclohexeneca'rboxylate hydrochloride, M. P. 130-133 C., issimilarly obtained from ethyl 2-benzoyl-A4-cyclohexene carboxylate.

Example XV.-p-Diethylaminoethyl Z-methyl-2-phenylcyclopropanecarbozylate.25 parts of ethyl diazoacetate in 18parts of a-methylstyrene has not been determinedbecause of itshygroylcyclohexanecarboxylate hydrochloride. 2'1 grams of2-pheny1cyclohexanecarboxylic acid, 2'1 parts of concentrated sulfuricacidand 160 parts of ethyl alcohol are refluxed 24 hours. The resultingreaction mixture is then poured into 500 parts of ice water andextracted with benzene.

Distillation ofthe resulting product gives ethyl2-phenylcyclohexanecarboxylate in good yields, this product coming overat 98-100 C./1 mm. Reesteriflcation of this with B-diethyiaminoethanol,as in Example I, gives the above product. It melts at 75-76" C; and ishygroscopic.

Example XIX.-p-Diethulaminoethul z-cu'clohexylcyclohexanecarbozylatehydrochloride-35 parts of Z-phenylbenzoic acid, 200 parts of glacial Iacetic acid and 0.4 part of Adams catalyst are shaken in a bomb withhydrogen at 50 lbs. until the theoretical amount is absorbed. Theresulting 2-cyclohexylcyclohexanecarboxylic acid is converted to theethyl ester, and then to the 7 above hydrochloride by thereesteriflcation proare refluxed for 12 hours at 130-140 C. The

product is distilled, and ethyl Z-methyl-Z-phnylcyclopropanecarboxylateis collected as the fraction boiling at 135-8 C./20 mm. 6 parts of this,

ester are refluxed with 5 parts of sodium hydrox-' ide in parts of ethylalcohol for 3 hours, after which the solution is acidified with 5%hydrochloric acid and the oil which separates is extracted with benzene.The benzene isremoved under vacuum, giving 5 parts of the free acid. 4.5parts of this acid, 9 parts of fi-diethylaminoethyl chloridehydrochloride, 17 parts of 10% alcoholic sodium ethcxide, and 40 partsof isopropanol is heated 24 hours at C. after which the isopropanol isremoved under vacuum and the residue is treated with 50 parts of 10%sodium carbonate and extracted with benzene. The benzene extract istreated with alcoholic hydrochloric acid with precipitation orfi-diethylaminoethyl 2 methyl 2 phenylcyclopropanecarboxylate, which onrecrystallization from butanone gives a white crystalline productmelting at 78-81 C.

Example XVL-p-Diethulaminoethul I-cyclohexylcyclohexanecarborylatehydrochloride-43 parts of p-diethylaminoethyll-phenylcyclohexanecarboiwlate hydrochloride, 125 parts of glacialacetic acid and 0.3 part of Adams catalyst are heated to 70 C. andshaken with hydrogen at 50 lbs. pressure until -100% of the theoreticalhydrogen is absorbed. The acetic acid is then removed by distillationand the residue recrystallized from butanone, giving the above productas a crystalline hydrochloride melting at 165-6 0., in good yields. Thisproduct may, also be prepared by reacting cyclohexyl bromide withcyclohexyl cyanide with the use or sodamide followed by alcoholysis andreesteriflcation as in Exam.-

pie 1. t

Example XVlL-p-Diethylamlnoethyl 1-cycl0- hexplcuclopentaneoarbozvlatehydrochloride. This product is obtained bythe reduction ofp-diethylaminoethyl 1-phenylcyclopentanecarboxylate hydrochloride, as inExample XV. It has a melting point of 126-128? C. A similar reduction ofp-diethylaminoethyl I-phenylcyclobutanecarboxylate hydrochloride givesthe corresponding cyclobutane compound as the hydrochloride melting at124-126 C.

Example XVIII.p-Dlethylaminoethyl Z-phencedure described in- Example Iusing diethylaminoethanol. It melts at -109 C.

Example XX. p-Triethylammoniumethyl-I- phenylcycloheaanecarboxylatebromide-Treatment of fi-diethylaminoethyl-l-phenylcyclohexanecarboxylate with ethyl bromide gives this product, which crystallizes inwhite platelets, M. P. 158-160 C. Similar treatment ofp-diethylaminoethyl 1 phenylcyclopentane carboxylate gives atriethylammoniumethyl-l-phenylcyclopentanecarboxylate bromide, M. P.150-152" C. 4

ExampleXXL-p-Diethylaminoethyl-Z-c1/clohexylcarbonylcyclohezanecarbemulatehydrochloride.Reesterification ot 2-cyclohexylcarbonylcyclohexanecarboxy acid ethyl ester with fi-diethylaminoethanol as in the precedingexamples gives this product. Onresolution by customary methods, tworacemic mixtures are obtained, one melting at -139 C., the other at132-136 0., each dissolving in about 3 parts 01 water. The melting pointof an approximately equal mixture is 122-126 C.

Products of the foregoing examples exhibit valuable pharmacologicalproperties, in particular having pronounced antispasmodic action onnormal smooth muscle. In addition, most of the products possess definitesedative action, in some cases sufilciently pronounced so thatsimultaneous administration of a sedative with them when'used forantispasmodic purposes is unnecessary. The compounds also have theproperty of neutralizing the physiological action or histamineindicating usefulness in combatting allergies. The compounds also haveusefulness as analgesics. oral or. parenteral, and ordinarily one of theacid addition salts is used.

In addition to the compounds described in the foregoing examples whichare intended primarily to describe suitable methods of preparation ofthe new compounds, the invention includes other nitrogen base alcoholesters of the aryl. aralkyl or cycloalkyl alicyclic, i. e., cycloalkylor cycloalkenyl, carboxy acids, including those in which one or both ofthe cyclic groups of the carboxy acid are further substituted by otherradicals, such as alkyl groups, chlorine or other halogen, hydroxygroups, or the like, or in which the substituent group attached to thealicycllc H carboxy acid is a condensed ring structure as Administrationof the compounds may be the ring structure, and may be further8ubstituted as previously stated.

The nitrogen base alcohdl roup used to esterify the carboxy acid may bederived from any one of a wide range of amino alcohols, includingprimary, secondary and tertiary amine derivatives, that is, compoundsinwhich 1, 2 or 3 of the hydrogen atoms of ammonia are replaced by alkylor alkylol groups or in which the nitrogen forms part of a ringstructure as in piperidine derivatives, and may contain more than oneamino group, as in the case of 1,3-bis-dietliylaminopropane-Z-Ol. andmay contain more than one alcoholiform hydroxyl group, as in the case of1-piperidino-2,3-propanediol, as well as'quaternary ammonium compoundscorresponding to such tertiary amino alcohols, but with the nitrogenfurther substituted, as by an alkyl, alicyclic, aralkyl or aryl group.Included among the compounds of the invention are the esters of thefollowing amino alcohols:

Diethylaminoethanol,

. Dimethylaminoethanol,

, p-Ethylaminoisopropanol,

3-Isopropylaminopropanol, Propanolamine, Ethanolamine,

' 4-Hydroxypiperidine,

and other amino alcohols, and the following quaternary ammoniumalcohols, named in terms oftheir cations: W Tiethylammonium ethanol,Diethylmethylammonium ethanol, Ethyldimethylammonium ethanol, 1-(Methylpiperidium) -2-hydroxy-propane, Ethyldimethylammoniumcyclohexanol,

, Diethylcyclohexylammonium ethanol, I

Benayldiethylammonium ethanol, Phenyldimethylammonium ethanol,

and other quaternary ammonium alcohols, with carboxy acids of thegeneralformula in whichR and R1 have the significance previo ously stated,including, among others, such acids 4-Phenylcyclohexanecarboxy acid,1-(Cyclohexeneyl-1,2) -cyclohexanecarboxy acid,1-Cyclohexylcyc1ohexanecarboxy acid, 2-Cyclohexylcyclohexanecarboxyacid, 4-Cyclohexylcyclohexanecarboxy acid, l-Benzylcyclopentanecarboxyacid, z-Methyl-l-phenylcyclopentanecarboxy acid,1-Pheny1cyclopentanecarboxy, acid, 1-Cyclohexylcyclopentanecarboxy acid,1-Cyclohexylcyclobutanecarboxy acid, 1-Phenylcyclobutanecarboxy acid,3-Methyl-l phenylcyclobutanecarboxy acid,2-Methyl-z-phenylcyclopropanecarboxy acid.

. formula l-Phenylcyclopropanecarboxy acid,1-alpha-Naphthalenecyclohexanecarboxy acid,1-alpha-Naphthalenecyclopentanecarboxy acid,z-Phenyl-z-hydrindenecarboxy acid,

5 2-Methyl-1-phenylcyclohexanecarboxy acid,

, 1-Cyclohexylcarbonylcyclohexanecarboxy acid,2-Cyclohexylcarbonylcyclohexanecarboxy acid, l-Benzylcyclohexanecarboxyacid,

l-Phenylcyclohexanecarboxy acid, z-Phenylcyclohexanecarboxy acid, g r

'z-(p-Methoxyphenyl) -A4 cyclohexenecarboxyl- 10 acid, 2-(3',4-Methylenedioxyphenyl) A4 'cyclohexene-carboxylic acid,

VZ-(p-Dimethylaminophenyl) A4 cyclohexene- I carboxylic acid.z-(p-cholorphenyl) 1A4 cyclohexenecarboiwlic acid, f

2-(aFuryl)-A4-cyclohexenecarboxylic acid,

z-(p-Nitrophenyl) A; cyclohexenecarboxylic aci1-Phenyl-A:-cyclohexenecarboxylic acid,1-Phenyl-Aa-cyclohexenecarboxylic acid, A2-Bicycl0(4,0,4)decene-lO-carboxylic acid,

'l-(p-Methoxyphenyl)cyclohexancarboxylic acid,

l-(pvchlorophenyl) cyclchexancarboigylic acid, 2- (p-Bromobenzoyl)cyclohexancarboxylic acid.

2-(Cyclohexan-2fi-one) cyclohexancarboxylic acid,1-Phenyl-3-methoxycyclobutanecarboxylic acid,

l-Phenyl-3-methoxycyclopentanecarboxylic acid,

1-Pheny1-3-bromocyclopentanecarboxylic acid,1-Phenyl-3-methoxycyclohexanecarboxylic acid,l-Phenyl-3-acetoxycyclohexancarboxylic acid, 2-Phenyl-4-chloro A4cyclohexenecarboxylic acid, 7 2-Phenyl-4,5-dichloro-A4cyclohexenecarboiwlic acid, 7 2-Phenyl-4-ethoxy A4 cyclohexenecarboxylicacid,

40 2 Phenyl- 4,5-dimethoxy A4 -'cycloheicenecarboxylic acid,2-Pheny1-2-methyl-Az-cyclohexenecarboxy acid,2-Phenyl-Aa-cyclohexenecarboxy acid, 2-(2',4'-dimethoxyphenyl) -A1cyclohexenecaroxy ac d.

We claim: i 1. Amino alcohol esters of carboxy acids of the RRiCOOH inwhich R and 31 are alicyclic.

2. Amino alcohol esters of carboxy acids of the formula RRICOOH m whichR1 iscycloalkyl and R is alicyclic.

3. Amino alcohol esters of carboxy acids of the formula RRICOOH in whichR1 is cycloalkenyl and R is alicyclic.

4. Amino alcohol esters of carboxy acids of the formula I-tlFhCOOH inwhich R and R1 are alicyclic and in which the 65 alicyclic ringstructure of R1 has 5 carbon atoms.

5. Amino alcohol esters of carboxy acids of the -formula RRiCOOH inwhich R1 is cyclopentyl and R is alicyclic.

RR COOI-I in which R and R1 are alicyclic.

'1. Diethylaminoethanol esters of carboxy acids Number Narne Date of theformula 2,219,706 Viaud Oct. 29, 1940 RR1COOH 2,404,588 Martin et a].July 23, 1946 in which R1 is cyclopentyl and R is alicyc lic. FOREIGNPATENTS 8. The B-diethylaminoethyl ester of l-cyclo- 1 1.hexybeyclopentane-carboxylic acid. Number Country Date 532,943 GreatBrltain Feb. 4, 1941 MARCUS GEORGE VAN CAMPEN 536 211 Greai Britain May7 1941 CHARLES HARMON TILFORD.

v 10 OTHER REFERENCES QE CITED Case, J. A. c. s). vol. 56, (1934) pp.715417. -The following referemces are of record in the Cheney et 9.1.;J. A. C. 8., vol. 64, (1942) pp. file of this patent? 970-973.

Number Name Date Burtner at 9.1., J. A. c. s.", 1101. 65, (1943) pp.

UNITED STATES PA'I'ENTS 15 26%268' 1,932,941 Guggenheim Oct. 24, 1933

